Abstract
Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease.
Highlights
The progression of soluble tau protein to neurofibrillary tangles (NFTs) is at the centre of many human neurodegenerative diseases, including Alzheimer's disease (AD) (Spillantini and Goedert, 2013)
We have shown that neurite orientation dispersion and density imaging (NODDI) indices correlated with histological measurements of tau pathology in grey matter regions in a mouse model of human tauopathy whereas traditional diffusion tensor imaging (DTI) indices of mean diffusivity (MD) and fractional anisotropy (FA) do not
Lower FA and higher MD in the corpus callosum (CC) have been reported in AD patients when compared with healthy volunteers (Bozzali et al, 2001) and more recent studies have found that reductions in the white matter FA in AD patients correlate with cerebrospinal fluid (CSF) AD biomarkers of total and phosphorylated tau (Amlien et al, 2013)
Summary
The progression of soluble tau protein to neurofibrillary tangles (NFTs) is at the centre of many human neurodegenerative diseases, including Alzheimer's disease (AD) (Spillantini and Goedert, 2013). Monitoring the progression of tau and its effect on neuronal reorganization due to tau-induced neurodegeneration in vivo is a key requirement in understanding the progression of AD and determining the efficacy of current therapeutic attempts to target tauopathies (de Calignon et al, 2012; Ahmed et al, 2014). To study these effects, we used an animal model of tau pathology: the TG mouse model which overexpresses a mutant form of human tau (P301L) resulting in tau accumulation in the form of NFTs largely restricted to the hippocampus, cortex, olfactory bulb, and striatum (Santacruz et al, 2005). Current understanding of tau propagation in synaptically connected brain regions is primarily obtained from invasive tissue measurements using immunohistological methods (Liu et al, 2012; Hardy and Revesz, 2012), which are restricted to single time point analyses and do not allow in vivo dynamic assessment of tissue remodelling due to pathology
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